Sickle cell disease (SCD) is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15% of African-Americans are homozygous for sickle cell disease, and 8% have sickle cell trait. Acute pain crisis, acute chest syndrome (ACS), and pulmonary hypertension are common complications of sickle cell anemia. Pulmonary hypertension (PH) has now been identified as a marker of mortality in adults with sickle cell disease. Sildenafil has been proven beneficial in pulmonary hypertension (PH) and recent phase I/II studies from the intramural National Institutes of Health (NIH) suggest it is well tolerated and efficacious in the SCD population. Furthermore, a number of recent studies have suggested that nitric oxide (NO) based therapies may have a favorable impact on sickle red cells at the molecular level and could improve the abnormal microvascular perfusion that is characteristic of sickle cell anemia. The project has 3 distinct components: 1. Screening Phase. Approximately 1000 subjects with sickle cell disease will be screened. Assessments will include historical and laboratory data, Doppler echocardiogram, 6-minute walk test, plasma/serum, and DNA for banking. 2. Main Interventional Trial. The randomized, double-blind, placebo controlled phase is designed to determine the effects of 16 weeks of sildenafil therapy on exercise endurance, cardiopulmonary hemodynamic parameters and symptoms in this patient population. The open-label follow-up phase is designed to provide up to an additional year of sildenafil therapy to subjects who complete the randomized, double-blind phase. 3. Observational Follow-up Study. Screened patients who do not qualify for participation in the main interventional trial may be contacted every 6-12 months for up to 3 years to assess major disease-related complications, including mortality. This is a multi-center study and had the following major objectives: 1. Screening to identify patients with sickle cell disease who have pulmonary hypertension and to create a cohort with an established cardiovascular phenotype linked to a biomarker and DNA repository 2. In a randomized, double-blind, placebo-controlled phase II/III trial, to determine the safety and efficacy of 16 weeks of sildenafil therapy on exercise capacity (six-minute walk distance), echocardiographic estimates of right ventricular systolic pressure, and symptoms in patients with sickle cell disease and pulmonary hypertension, defined by TRV greater than 2.7 meters per second (m/s) 3. Via a right heart catheterization in subjects with more severe pulmonary hypertension (TRV stratum), to evaluate and compare the acute hemodynamic effects of inhaled nitric oxide and of oral sildenafil at rest in the catheterization laboratory and to determine the changes in hemodynamics after 16 weeks of sildenafil therapy 4. To evaluate prospective clinical outcomes in the subjects participating in the Observational Follow-up Study 5. To provide subjects with open-label sildenafil for up to one year after completion of the Main Interventional Trial and to evaluate the long term safety of sildenafil in this population. The primary endpoint in the Main Interventional Trial is change in six minute walk distance across the 16 week double-blind phase. Up to 1000 subjects will be screened based on medical history, physical examination, laboratory testing, transthoracic Doppler-echocardiography, and 6MW test. All consented subjects in this cohort will provide plasma and serum for storage and measurement of BNP and DNA for a repository, and will be followed prospectively in the Observational Follow-up Study (OFS). Patients found to have a screening TRV of greater than 2.7 m/s will be invited to participate in the Main Interventional Trial (MIT). Upon repeat echocardiogram at baseline, patients with TRVs greater than 2.7 m/s who meett all inclusion/exclusion criteria will be enrolled in the 16 week, randomized, double-blind, placebo-controlled trial of sildenafil versus placebo: the Main Interventional Trial (MIT). The study will randomize 132 subjects in MIT. Subjects will be stratified and randomized based on TRVs. One-half of the subjects, those with TRV greater than or equal to 3.0 m/s, will also be evaluated with right heart catheterization (RHC) before and after 16 weeks of the intervention. Study assessments will occur at weeks 6, 10, and 16 or early withdrawal. The primary endpoint is change in 6MW distance across this study phase. Secondary endpoints include non-invasive estimation of pulmonary artery systolic pressure by transthoracic Doppler-echocardiography, plasma NT-BNP levels, cardiovascular and sickle cell related symptoms and events, and quality of life scores. Recruitment into the Screening Phase and MIT is expected to extend for approximately 13 months or longer. Subjects who complete the double-blind phase will be eligible to participate in the Open-label Follow-up Phase and will be treated with sildenafil for up to 1 additional year;only AE data will be collected during this period. This study was approved by the NHLBI Institutional Review Board December 26, 2007 and we began screening and enrolling subjects on December 31, 2007. At the NIH site, we screened 131 subjects: 114 subjects were enrolled in the Observational Follow-up;17 subjects were randomized into the Main Interventional Trial;and 13 subject continued to Open Lable Phase after completing the MIT. On July 8, 2009 all sites were notified that based on recommendations from the DSMB all activity in the MIT and Open Label Phase of the study was to end. This recommendation was based on an unmasked report to the DSMB that described more treatment-emergent Serious Adverse Events (SAEs) in the Sildenafil group during the MIT. Then on August 13, 2009 all sites were informed that the FDA and put the entire study on Clinical Hold. Currently, all follow-up visits have been completed and the study is now open to data analysis only. Preliminary analysis of the data from the truncated study indicate that primary outcome was not positive. Additional secondary outcome analysis continues.